5-hydroxy-3-(6-hydroxy-2-naphthyl) pentanoic acid lactones



Patented ug. 19, .1.952

Searle & Co., Chicago,

Illinois No Drawing. Application septenioeir16;11949,.v` .wseria1No.1i6;215 Y. f vclaims. (012601-349 'L 1y This invention relatesto lctones" of thenaphthalene and` polyhydronaphthalene series. havingthe general structural formula' Relais., `-'CH |1H-oo wherein X ishydrogen, lower alkyl, or lower acyl; Rand vR.' are hydrogen or loweralkyl; and Y is hydrogen or lower alkyl; and wherein thenaphthalene-nucleusmay be completely aromatic or partially or completelyre-ecluced.v This inven.,

tion'` also `relates toA methods `for* preparing .such lactonesi` In theforegoing structural formulalX'repref.

sents hydrogen or lower alkyl radicals such as methyl, ethyl, propyl,isopropyl, and butyl, aralkyl radicals such asl benzyl, benzhydryl,xenylmethyl, phenethyl, orvnaphthylmethyl, or alkanoyl radicals such asacetyl, propionyl. and butyryl, and related acyl radicals suchasbenzoyl, cuccinyl, phthalyl, henzeriesulfonyl, toluenesulfonyl, and thelike. RSR", and Yrepresent hydrogen and lower alkyl radicals such asmethyl, ethy1'. propyl, isopropyl; and butyl.

Compoundsof the foregoing formula. are 'Lisehormones. Compoundsof thisinvention arefalso useful in the preparation of. complex Striod-lik'lmolecules andrel'ated polynclar compounds.

The compounds of this vinvention are prepared.

by. reacting a -nophthm derivetiifapeferaiily e -naphth'yl ether, withan acid halide orl anhydride derived from anacid ofthe following generalformula Rl oHQHeI Iwo-Coon' Ile' K ferrie chloride, boron trifluoride,hydrogen fluo'- ride, and the like in a solvent such as nitrobenzeneor-otherfvsolvent;whichiiniluences, substitution zin resulting ketonewhich has the formula wherein-R andR- havethe foregoing meanings and Halrepresentsv halogenlv suchl as-chlOrin, bromine; or iodine; The'-condensation is carried: out they presencevofa'Fridel-Crafts catalyst'such asv aluminum chloride,` stannic4 chlor`ide 111 a corporation.' of

is'then condensed with eri-ester ofeehoiogeneted in the presenceogranulatedfzin'c, Zinc Adiist or foil, zinc-copper powder,iiag'nes'iuiv onzi'xic amalgam'.l The resulting condensation product',r

D uringfthis sapniiication treatment the esterl linkage is cleavedtoacarboxylic eroici-"groupand-l the' halogen is split ofr'fwith aformation of"a ;hY`-' droxylradical. If X A'represents 'an `YyacylVradical this may y'also besaponndat; the saine time; The unsaturatedhydroxy acidi'ssubseduntlyrefduced toa saturated acid" which; under'the; 111-' fluen'ce ofifacidforlns' the desired lactOne; The reduction,`can `be carried' out' byv a variety "of methods; ^Forl exaiiip1c', theunsaturated." acidy may' b e reduced oataltioally' in the preseie lofRainey nickel in aqueous,,alkali or in'an organic solvent;V I t may alsobe reduced by ofa'fi'i'vojble metal catalyst such asV platinum oxide;palladium. back, and. 'palladium on` charcoal' or" other' sup,- port.The reduction-.can be. carried outiby ohemi: cal, means,v asl vforxainplry, lfe'iiiictio'ri withV sodium amalgam in aqueous. alkali'. Theresulting' lactone can ,thereafter bev dealkyl'ated 'r- .dearal acidsfin organic solvents, and related' methods.

The` dearalkylation. can be .(if/.lid out. .similarly tothe.ydealkylationvor can beacconplished by hydrogenolysis, as,.fvor.eianp1e,fwith apall'adiim orj platinum; cataly tandhydrogenjatglG-.IOQ p s =i andatZO-lll., l 1

The following 'examples i1' usi-rete in detail'.

- parts of'ether.

ether, 172 parts of chlorotrimethylacetyl chloride,

the compounds of this inv and 840 parts of nitrobenzene is cooled toabout d C. To this solution are added gradually and` With emcientagitation 267 parts of anhydrous aluminum chloride in nely powderedform, the

reaction mixture being kept at approximately ice temperature.

precipitate of 3 chloro 2,2 dimethyl 1 (6- dmethoxy-2-naphthyl)-l-propanone is obtained. Thiscompound melts lat85-85.6 C. upon recrystallization from` benzene and petroleum ether.A Ithas the formula Y Y TCH: Y

' 1oni-fill;Cnt-*.01 Y

'Example 2- Zinc-amalgam isfprepared by treating 200 parts of 40-meshzinc metal with 1000 parts of 3% hydrochloric acid Asolution containing2 Vparts of mercurio .chloridelf 'Thee 'resulting product is WashedyWith water, alcohol, andether. One half of the.'arxiaig'matedA is addedtoalso'lution f 3'05 parts of, 'Siemen-'2 2 z .dimethyl 9 1.- 1(6-rnetlioxyf Z-'naphthyD .-l1-propa'none inv 66,0' parts of dry benzene.The" mixtur'e is reluxed' and agitated 'and' '.18 .partsoi 'ethyl'bromoacetate in 180`parts'o'f 'ether are added. ','Ihe' mixturje isagitated' and reiiuxed for' three" hours, the. remainderl 'off theamalgamated zinc 'being added; atv 3D-minuteintervals. Afterione Vhourof reluxing another portion of "18 @parts vof ethylV bromoacetate and'180 parts'of ether arejadded. The reaction mixture istreatedV with 2091lpartsV of acetic acidin methanol' followedby1400 The .etherealpha'sejsseparated and Washed With2000 parts l orN vsulfuric acid, withWater;"witht;3'% aqueous 'ammonia until the vvvajshjingslj.afrerjnollonger g colored',l and their with ,vv'atenl lThev ether solution'`Vis, dried. andv evaperatedi 'and the" 'residue' its" .taken 'uni in "500parts j "of acetic d anh ,ide-and f heated at 'about 100?'1C' ..fo1f1;2.hprS'-, Thief "aetc i anhydride iS then evaporated underreducedpress'ureat 90 C. andgj395` parts oflmeth'anol and 315 parts of 26% causticpotashjsolution are-added and the resulting'j'alkaline solutio'n is refluxed `for two hours. The reactionV mixture'V chilled,V `ldiluted ,t/ith2.50.0 .parts .0f water, andisxtraetef Wiili ther- The reaction .mixtureisrallowed to stand at room temperature for about. 24 hours. It is thenquenched in an excess of benzene and acetone. -melts at 189-190 C. whenpure. It has the The aqueous phase is separated, made strongly acid withsulfuric acid, and then extracted with ether. The ether extract isWashed with water, with 3% sodium bicarbonate solution and with water.The bicarbonate extract is acidified and chilled. The crystallineprecipitate of -hydroxy- 4,4 ,-.dimethyl 3 (6 methoxy 2 naphthyl)Z-pentenoic acid is separated, Washed With aqueous alcohol, andrecrystallized from a mixture of The acid so obtained formula (IJHSOHa-C-CHZOH Example 3 11.5 parts of 5 hydroxy 4,4 dimethyl 3- (6 methoxy2 naphthyl) 1-2. '-jpentenoic acid are dissolved in 2501partsgfof 'watercontaining 13.7 parts of 26%' caustic potash solution. To this solutionare added 600 parts of 2% sodium amalgam. The resulting mixture isagitated with intermittent heating at about -100 C. for 30 minutes. Thesolution is separated by decantation, Washed with ether, and then madestrongly acid with sulfuricacid. The acid solution is extracted withether and the ether solution is Washed With water, With 3% sodium'bicarbonate solution, andlthen with Water.V AItis then treated with atrace of acetic acd'andthe ether is removed by evaporation.- 'I'heresidue is crystallized from aqueous methanol and-thelactone of5-hydroxy-4,4'dimethyl-3-(G-methoxy-Z- naphthyl) pentanoic acid melts at150.5151.5 C. Ithastlieformulaf-A Y i f CHs "'L' K- CERO-n Y Example. 4A Y l 3 parts of the foregoingv lactone. are fused forz 2 hours at 190C.,With 15 parts of 'pyridine hy-v drochloridexThe melt is. then vcooledand taken up in 1400 parts-of.etherand'1500 parts.of ',3% hydrochloricacid; ',The `eth'er"solution is separated, washedpwith Water; dried,and` evaporated., The residue is e'rystallized"from` aqueous methanolandy from a mixture ofjacetone and cyclo-` hexane- The.' latone, 0f.fhydroXY-lfll-dimthyl. 3-(6-hydroxy-'2-naphthyl) -p'entanoicfacid-'.jmelts' at192 '193c. f j.

A 4 parts of 3minore-21,2 dimahyi-14e-mdium- 2-naphthy1)1propanone in103 parts of metha total of 20 parts of ethyl a-bromopropicnate in thepresence of 20 parts of amalgamated zinc in dry benzene and ether,according to the method of Example 2. The hydroxy ester is isolated asfollows: The reaction mixture is diluted with acetic acid in methanoland then extracted with ether. The ether extract is washed with dilutesulfuric acid, Iwith water, with dilute ammonia water and finally withwater. The dried ether extract is evaporated, yielding the hydroxyester. This is treated with 25 parts of acetic anhydride at 90-95o C'.for 2 hours, and then evaporated under vacuum. The residue of theresulting unsaturated ester is reiiuxed for 2 hours in 40% potassiumhydroxide solution in 70% methanol. The methanol is removed bydistillation and the chilled alkaline solution is diluted with water andextracted with ether. The alkaline solution is then acidified andextracted with ether. The ether extract is Washed with water and thenextracted with 3% sodium bicarbonate solution. The bicarbonate extractis chilled and acidied. On standing, colorless crystals of5-hydroxy-2,4,4-trimethyl-3-(fi-methoxy 2 naphthyl) 2 pentenoic acidseparate. These are separated, washed with lwater and dried. The acidhas the formula Example '7 10 parts of 5-hydroxy-2,4,4-trimethyl-B(6-methoxy-Z-naphthyl) -Z-pentenoic acid are dissolved in 150 parts ofglacial acetic acid and hydrogenated in the presence of 0.2 parts ofplatinum oxide at 50 C. andv at 35-50 lb. hydrogen pressure. After thehydrogen uptake ceases the solution is iiltered and evaporated undervacuum. The residue is taken up in dilute alkali, ltered, acidied andthen extracted with ether. The ether extract is washed with water,dried, treated with a small amount of glacial acetic acid and evaporatedto dryness. The crystalline residue of the lactone of -hydroxy-ZAA-trimethyl-3-(6-methoxy -2- naphthyl) pentanoic acid is separated anddried. 'This substance has the formula I CHi-C-oHz-o I l CH-(llH-C O CH3CHaO Example 8 3 parts of the lactone of 5-hydroxy-2,4,4trimethyl-S-(G-methoxy -2- naphthyDpentanoic acid are demethylated byfusion with parts of pyridine hydrochloride as in Example 4. The mixtureis then partitioned between 150 parts I claim: l. A compound of theformula R R' n n-(IlH-o -GH-CIlH-(IBO Y XO- wherein X is a member of thegroup consisting of hydrogen, lower alkyl and lower acyl radicals, RandR' are members of the group consisting of hydrogen and lower alkylradicals and Y is a member of the group consisting of hydrogen and loweralkyl radicals.

2. A compound of the formula wherein R and R are lower alkyl radicals.

3. A compound of the formula l R-C-CHa-O l I CH-CHi-C O wherein R is alower alkyl radical.

4. A compound as in claim 3 wherein R is a methyl radical.

5. A compound of the formula wherein X is a lower alkyl radical and Risa lower alkyl radical.

6. A compound as in claim 5 wherein X is a lower alkyl radical and R isa methyl radical.

7. A compound as in claim 5 wherein X and R are methyl radicals.

- MAX N. HUFFMAN.

No references cited.

Thev

1. A COMPOUND OF THE FORMULA